Increased glucose variability is associated with atrial fibrillation after coronary artery bypass.

BACKGROUND: Elevated preoperative hemoglobin A1c (HbA1c) is a predictor of poor outcomes following coronary artery bypass grafting (CABG), but the role of increased postoperative glucose variability (GV) is unknown. We hypothesized that short-term postoperative GV is associated with an increased risk of postoperative atrial fibrillation following isolated CABG. METHODS: Multicenter retrospective study of 2073 patients who underwent isolated CABG from January 2012 to March 2018. Postoperative GV in the first 24 hours was measured by standard deviation, coefficient of variation, and mean amplitude of glycemic excursions. Multivariate logistic regression assessed the independent association of GV with postoperative atrial fibrillation. RESULTS: A total of 2073 patients met the study criteria, and 446 patients (21.5%) developed postoperative atrial fibrillation. Using multivariate logistic regression to adjust for covariates, postoperative atrial fibrillation was associated with increased 24-hour GV (odds ratio [OR] = 1.16, 95% confidence interval [CI], 1.05-1.27, P < 0.01) and increased 24-hour mean glucose (OR = 1.14, 95% CI, 1.08-1.21, P < 0.01). Thus, for every 10% increase in 24-hour GV or 10 mg/dL increase in mean glucose, there was a 16% or 14% increased risk of postoperative atrial fibrillation respectively. CONCLUSIONS: Increased 24-hour GV and mean glucose are predictors of atrial fibrillation after CABG. Preoperative HbA1c is not a risk factor for postoperative atrial fibrillation after adjusting for postoperative mean glucose and GV. Further investigation is needed to determine the relationship between adherence to strict glucose control and adverse events following CABG.

Patients With Diabetes and Chronic Liver Disease Are at Increased Risk for Overall Mortality: A Population Study From the United States.

IN BRIEF Chronic liver disease (CLD) and type 2 diabetes have both been linked to increased morbidity and mortality. In this study, the impact of CLD and diabetes on all-cause mortality was quantified at the population level using U.S. population data. Both type 2 diabetes and CLD were found to be independently associated with increased mortality (age-adjusted hazard ratio [aHR] 1.98 and 1.37 for diabetes and CLD, respectively), and having both diabetes and CLD substantially increased the risk of mortality (aHR 2.41).

Vaccination against hepatitis A and B in patients with chronic liver disease and type 2 diabetes: has anything changed?

BACKGROUND & AIMS: Given the severity of acute hepatitis in patients with chronic liver diseases (CLD) and patients with type 2 diabetes (DM), most of these patients are recommended to be vaccinated. The aim is to assess the recent changes in HAV and HBV vaccination rates in patients with CLD and DM in the U.S. using the most recent population data. METHODS: We used the National Health and Nutrition Examination Surveys (NHANES) cycles 2009-2012 and 2013-2014, and compared those to previous cycles (1999-2004 and 2005-2008). RESULTS: In general U.S. population, the rates of quality measure (QM, serologic immunity or history of vaccination) for HBV increased from 31.9% in 1999-2004 to 49.5% in 2013-2014 (P < 0.0001), synchronously with an increase in self-reported HBV vaccination: from 24.4% to 41.3% (P < 0.0001). A similar increase was noted for HAV: 12.0% in 1999-2004 to 33.4% in 2013-2014 in vaccination, 44.0% to 52.4% in HAV QM (all P < 0.0001). Greater recent increases in HBV QM were noted in non-HBV CLD patients: 34.7% to 56.8% in HBV QM and 22.7% to 51.1% in HBV vaccination (all P < 0.0001), while the changes in patients with diabetes were similar to those in general U.S. population despite the recent CDC recommendation (for the age 19-59): 31.0% to 45.1% (P = 0.007) in HBV QM, and 22.3% to 39.0% (P = 0.0004) in HBV vaccination. CONCLUSIONS: Despite recommendations, HAV and HBV vaccination rates in patients with CLD and DM remain relatively low. Better vaccination strategies for these high risk patients should be undertaken.

Pioglitazone for diabetes prevention in impaired glucose tolerance.

BACKGROUND: Impaired glucose tolerance is associated with increased rates of cardiovascular disease and conversion to type 2 diabetes mellitus. Interventions that may prevent or delay such occurrences are of great clinical importance. METHODS: We conducted a randomized, double-blind, placebo-controlled study to examine whether pioglitazone can reduce the risk of type 2 diabetes mellitus in adults with impaired glucose tolerance. A total of 602 patients were randomly assigned to receive pioglitazone or placebo. The median follow-up period was 2.4 years. Fasting glucose was measured quarterly, and oral glucose tolerance tests were performed annually. Conversion to diabetes was confirmed on the basis of the results of repeat testing. RESULTS: Annual incidence rates for type 2 diabetes mellitus were 2.1% in the pioglitazone group and 7.6% in the placebo group, and the hazard ratio for conversion to diabetes in the pioglitazone group was 0.28 (95% confidence interval, 0.16 to 0.49; P<0.001). Conversion to normal glucose tolerance occurred in 48% of the patients in the pioglitazone group and 28% of those in the placebo group (P<0.001). Treatment with pioglitazone as compared with placebo was associated with significantly reduced levels of fasting glucose (a decrease of 11.7 mg per deciliter vs. 8.1 mg per deciliter [0.7 mmol per liter vs. 0.5 mmol per liter], P<0.001), 2-hour glucose (a decrease of 30.5 mg per deciliter vs. 15.6 mg per deciliter [1.6 mmol per liter vs. 0.9 mmol per liter], P<0.001), and HbA(1c) (a decrease of 0.04 percentage points vs. an increase of 0.20 percentage points, P<0.001). Pioglitazone therapy was also associated with a decrease in diastolic blood pressure (by 2.0 mm Hg vs. 0.0 mm Hg, P=0.03), a reduced rate of carotid intima-media thickening (31.5%, P=0.047), and a greater increase in the level of high-density lipoprotein cholesterol (by 7.35 mg per deciliter vs. 4.5 mg per deciliter [0.4 mmol per liter vs. 0.3 mmol per liter], P=0.008). Weight gain was greater with pioglitazone than with placebo (3.9 kg vs. 0.77 kg, P<0.001), and edema was more frequent (12.9% vs. 6.4%, P=0.007). CONCLUSIONS: As compared with placebo, pioglitazone reduced the risk of conversion of impaired glucose tolerance to type 2 diabetes mellitus by 72% but was associated with significant weight gain and edema. (Funded by Takeda Pharmaceuticals and others; ClinicalTrials.gov number, NCT00220961.).

Pioglitazone slows progression of atherosclerosis in prediabetes independent of changes in cardiovascular risk factors.

OBJECTIVE: To determine whether changes in standard and novel risk factors during the Actos Now for Prevention of Diabetes trial explained the slower rate of carotid intima media thickness (CIMT) progression with pioglitazone treatment in persons with prediabetes. METHODS AND RESULTS: CIMT was measured in 382 participants at the beginning and up to 3 additional times during follow-up of the Actos Now for Prevention of Diabetes trial. During an average follow-up of 2.3 years, the mean unadjusted annual rate of CIMT progression was significantly (P=0.01) lower with pioglitazone treatment (4.76×10(-3) mm/year; 95% CI: 2.39×10(-3)-7.14×10(-3) mm/year) compared with placebo (9.69×10(-3) mm/year; 95% CI: 7.24×10(-3)-12.15×10(-3) mm/year). High-density lipoprotein cholesterol, fasting and 2-hour glucose, HbA(1c), fasting insulin, Matsuda insulin sensitivity index, adiponectin, and plasminogen activator inhibitor-1 levels improved significantly with pioglitazone treatment compared with placebo (P<0.001). However, the effect of pioglitazone on CIMT progression was not attenuated by multiple methods of adjustment for traditional, metabolic, and inflammatory risk factors and concomitant medications, and was independent of changes in risk factors during pioglitazone treatment. CONCLUSIONS: Pioglitazone slowed progression of CIMT, independent of improvement in hyperglycemia, insulin resistance, dyslipidemia, and systemic inflammation in prediabetes. These results suggest a possible direct vascular benefit of pioglitazone.

Molecular bases of plant resistance to arthropods.

Arthropod-resistant crops provide significant ecological and economic benefits to global agriculture. Incompatible interactions involving resistant plants and avirulent pest arthropods are mediated by constitutively produced and arthropod-induced plant proteins and defense allelochemicals synthesized by resistance gene products. Cloning and molecular mapping have identified the Mi-1.2 and Vat arthropod resistance genes as CC-NBS-LRR (coiled coil-nucleotide binding site-leucine rich repeat) subfamily NBS-LRR resistance proteins, as well as several resistance gene analogs. Genetic linkage mapping has identified more than 100 plant resistance gene loci and linked molecular markers used in cultivar development. Rice and sorghum arthropod-resistant cultivars and, to a lesser extent, raspberry and wheat cultivars are components of integrated pest management (IPM) programs in Asia, Australia, Europe, and North America. Nevertheless, arthropod resistance in most food and fiber crops has not been integrated due primarily to the application of synthetic insecticides. Plant and arthropod genomics provide many opportunities to more efficiently develop arthropod-resistant plants, but integration of resistant cultivars into IPM programs will succeed only through interdisciplinary collaboration.

Euglycemic diabetic ketoacidosis in the era of SGLT-2 inhibitors.

Euglycemic diabetic ketoacidosis (EDKA) is an emerging complication of diabetes associated with an increasing use of sodium-glucose transporter type 2 (SGLT-2) inhibitor drugs. This review highlights the growing incidence of EDKA and its diagnostic challenges due to the absence of hallmark hyperglycemia seen in diabetic ketoacidosis (DKA). The paper presents a classification system for the severity of EDKA, categorizing it into mild, moderate, and severe based on serum pH and bicarbonate levels. Another classification system is proposed to define stages of EDKA based on anion gap and ketones at the time of diagnosis and during the treatment period. A treatment algorithm is proposed to guide clinicians in managing EDKA. This treatment algorithm includes monitoring anion gap and ketones to guide insulin and fluid management, and slower transition to subcutaneous insulin to prevent a relapse. Increased awareness of EDKA is essential for a timely diagnosis because an early diagnosis and treatment can improve clinical outcomes.

Detrimental and neutral effects of a wild grass-fungal endophyte symbiotum on insect preference and performance.

Seed-borne Epichloë/Neotyphodium Glenn, Bacon, Hanlin (Ascomycota: Hypocreales: Clavicipitaceae) fungal endophytes in temperate grasses can provide protection against insect attack with the degree of host resistance related to the grass-endophyte symbiotum and the insect species involved in an interaction. Few experimental studies with wild grass-endophyte symbiota, compared to endophyte-infected agricultural grasses, have tested for anti-insect benefits, let alone for resistance against more than one insect species. This study quantified the preference and performance of the bird cherry oat-aphid, Rhopalosiphum padi (L.) (Hemiptera: Aphididae) and the cereal leaf beetle, Oulema melanopus (L.) (Coleoptera: Chrysomelidae), two important pests of forage and cereal grasses, on Neotyphodium-infected (E+) and uninfected (E-) plants of the wild grass Alpine timothy, Phleum alpinum L. (Poales: Poaceae). The experiments tested for both constitutive and wound-induced resistance in E+ plants to characterize possible plasticity of defense responses by a wild E+ grass. The aphid, R. padi preferred E- over E+ test plants in choice experiments and E+ undamaged test plants constitutively expressed antibiosis resistance to this aphid by suppressing population growth. Prior damage of E+ test plants did not induce higher levels of resistance to R. padi. By contrast, the beetle, O. melanopus showed no preference for E+ or E- test plants and endophyte infection did not adversely affect the survival and development of larvae. These results extend the phenomenon of variable effects of E+ wild grasses on the preference and performance of phytophagous insects. The wild grass- Neotyphodium symbiotum in this study broadens the number of wild E+ grasses available for expanded explorations into the effects of endophyte metabolites on insect herbivory.

Clinical assessment for high-risk patients with non-alcoholic fatty liver disease in primary care and diabetology practices.

BACKGROUND: Primary care practitioners (PCPs) and diabetologists are at the frontline of potentially encountering patients with NASH. Identification of those at high risk for adverse outcomes is important. AIM: To provide practical guidance to providers on how to identify these patients and link them to specialty care. METHODS: US members of the Global Council on NASH evaluated the evidence about NASH and non-invasive tests and developed a simple algorithm to identify high-risk NASH patients for diabetologists and primary care providers. These tools can assist frontline providers in decision-making and referral to gastroenterology/hepatology practices for additional assessments. RESULTS: The presence of NASH-related advanced fibrosis is an independent predictor of adverse outcomes. These patients with NASH are considered high risk and referral to specialists is warranted. Given that staging of fibrosis requires a liver biopsy, non-invasive tests for fibrosis would be preferred. Consensus recommendation from the group is to risk-stratify patients based on metabolic risk factors using the FIB-4 as the initial non-invasive test due to its simplicity and ease of use. A FIB-4 score ≥1.3 can be used for further assessment and linkage to specialty care where additional technology to assess liver stiffness or serum fibrosis test will be available. CONCLUSION: Due to the growing burden of NAFLD and NASH, PCPs and diabetologists are faced with increased patient encounters in their clinical practices necessitating referral decisions. To assist in identifying high-risk NASH patients requiring specialty care, we provide a simple and easy to use algorithm.

What are the best options for controlling prandial glycemia?

Epidemiologic studies suggest that postprandial hyperglycemia is more strongly linked to an increased risk for cardiovascular events than fasting or preprandial glucose levels. Although the results of prospective randomized studies proving causation of this finding are mixed, clinicians have given increased attention to target therapy to postprandial glucose than in the past. Rapid-acting insulin analogues, glucagon-like peptide-1 agonists, dipeptidyl peptidase-4 inhibitors, and acarbose all target the postprandial glucose levels. This wide range of therapies allows the clinician to mix and match agents of different classes to target the fasting, preprandial, and postprandial glucose to optimize the daily glucose pattern and reduce the risk of diabetic complications.

Actos Now for the prevention of diabetes (ACT NOW) study.

BACKGROUND: Impaired glucose tolerance (IGT) is a prediabetic state. If IGT can be prevented from progressing to overt diabetes, hyperglycemia-related complications can be avoided. The purpose of the present study was to examine whether pioglitazone (ACTOS) can prevent progression of IGT to type 2 diabetes mellitus (T2DM) in a prospective randomized, double blind, placebo controlled trial. METHODS/DESIGN: 602 IGT subjects were identified with OGTT (2-hour plasma glucose = 140-199 mg/dl). In addition, IGT subjects were required to have FPG = 95-125 mg/dl and at least one other high risk characteristic. Prior to randomization all subjects had measurement of ankle-arm blood pressure, systolic/diastolic blood pressure, HbA1C, lipid profile and a subset had frequently sampled intravenous glucose tolerance test (FSIVGTT), DEXA, and ultrasound determination of carotid intima-media thickness (IMT). Following this, subjects were randomized to receive pioglitazone (45 mg/day) or placebo, and returned every 2-3 months for FPG determination and annually for OGTT. Repeat carotid IMT measurement was performed at 18 months and study end. Recruitment took place over 24 months, and subjects were followed for an additional 24 months. At study end (48 months) or at time of diagnosis of diabetes the OGTT, FSIVGTT, DEXA, carotid IMT, and all other measurements were repeated.Primary endpoint is conversion of IGT to T2DM based upon FPG >or= 126 or 2-hour PG >or= 200 mg/dl. Secondary endpoints include whether pioglitazone can: (i) improve glycemic control (ii) enhance insulin sensitivity, (iii) augment beta cell function, (iv) improve risk factors for cardiovascular disease, (v) cause regression/slow progression of carotid IMT, (vi) revert newly diagnosed diabetes to normal glucose tolerance. CONCLUSION: ACT NOW is designed to determine if pioglitazone can prevent/delay progression to diabetes in high risk IGT subjects, and to define the mechanisms (improved insulin sensitivity and/or enhanced beta cell function) via which pioglitazone exerts its beneficial effect on glucose metabolism to prevent/delay onset of T2DM. TRIAL REGISTRATION: clinical trials.gov identifier: NCT00220961.

Medical Management of the Diabetic Patient.

Diabetes prevalence is increasing in the United States. As of 2017, 30.3 million people in the United States have diabetes (9.4% of population). Of these, an estimated 7.2 million persons are undiagnosed. Prediabetes, a condition that is associated with peripheral neuropathy and is a precurser to diabetes, affects 83.1 million or 33.9% of adults in the United States. Diabetes is most commonly diagnosed by fasting plasma glucose or by an A1C test. An oral glucose tolerance test can also be used, but its use is primarily restricted to research settings.

Better glycemic control in the hospital: beneficial and feasible.

Hospitalized patients fare better if their blood glucose levels are strictly controlled. To manage blood glucose effectively, hospitals need to set up formal programs. Attending physicians, endocrinologists, and nurses need to work as a team. Standardized forms with management guidelines are valuable.

Flies (Diptera: Muscidae: Calliphoridae) are efficient pollinators of Allium ampeloprasum L. (Alliaceae) in field cages.

In conjunction with efforts to identify efficient insect pollinators for seed multiplication of cross-pollinated plant species stored and maintained by USDA-ARS Western Regional Plant Introduction Station (WRPIS), experiments were conducted to assess and compare the efficiency of the house fly, Musca domestica L. (Diptera: Muscidae), and Calliphora vicina Robineau-Desvoidy (Diptera: Calliphoridae), and different densities of each fly species, to pollinate leek, Allium ampeloprasum L., plant inventory (PI) accessions in field cages for seed yield maximization and high germination. Cages with flowering plants were exposed to 0 flies or stocked with 100, 250, and 500 M. domestica or C. vicina pupae per week for 6 (2002) and 7 (2004) wk. Seed yield (weight per cage) increased linearly as fly densities (C. vicina or M. domestica) increased from 0 to 500 pupae per week, with 500 fly cages averaging 340.7 g (C. vicina) and 70.5 g (M. domestica) of seed in 2002 (PI 368343) and 615.3 g (PI 168977) and 357.5 g (PI 368343) in 2004 when only the C. vicina was used. For 0, 100, and 250 fly cages, seed yields averaged between 2.3 and 175.3 g in 2002 and 10.7 and 273.1 g in 2004. Mean 100-seed weights between treatments ranged narrowly between 0.4 and 0.5 g in 2002 and 0.3 and 0.4 g in 2004, and germination rates of seed lots from "fly cages" were mostly > or =80% in both years. The C. vicina is an efficient and cost-effective pollinator ($388.97 for pupae and shipping, compared with $2,400 for honey bee, Apis mellifera L. [Hymenoptera: Apidae], nuclei) for caged leek accessions, with 250 and 500 C. vicina pupae per week required to produce sufficient seed (130 g) to fill an accession storage bag in the WRPIS gene bank.

Inhaled insulin improves glycemic control when substituted for or added to oral combination therapy in type 2 diabetes: a randomized, controlled trial.

BACKGROUND: Patients with type 2 diabetes who do not achieve glycemic control with oral agent therapy eventually require insulin. OBJECTIVE: To determine the effect on glycemic control of inhaled insulin alone or added to dual oral therapy (insulin secretagogue and sensitizer) after failure of dual oral therapy. DESIGN: Open-label, randomized, controlled trial. SETTING: 48 outpatient centers in the United States and Canada. PATIENTS: 309 patients with type 2 diabetes, no clinically significant respiratory disease, and hemoglobin A(1c) level of 8% to 11% who were receiving dual oral therapy. MEASUREMENTS: Primary end point was change in hemoglobin A(1c) level from baseline to 12 weeks. Secondary outcomes included hemoglobin A(1c) level less than 8% and less than 7%, hypoglycemia, weight, lipid levels, pulmonary function, insulin antibody binding, and adverse events. INTERVENTION: Inhaled insulin (Exubera; Pfizer Inc. [New York, New York], sanofi-aventis Group [Paris, France], and Nektar Therapeutics [San Carlos, California]), titrated to blood glucose, administered alone (n = 104) or added to dual oral agents (n = 103) versus oral therapy alone (n = 99). RESULTS: Reductions in hemoglobin A(1c) level were greater with inhaled insulin. Adjusted treatment group differences for inhaled insulin plus oral agents and inhaled insulin alone compared with continued oral agent therapy were -1.67 percentage points (95% CI, -1.90 to -1.44 percentage points; P < 0.001) and -1.18 percentage points (CI, -1.41 to -0.95 percentage point; P < 0.001), respectively. Hemoglobin A(1c) level less than 7% was achieved by 32% (inhaled insulin plus oral agents) and by 1% (oral agent therapy) of patients (adjusted odds ratio, 44.7 [CI, 6.0 to 335.2]). Hypoglycemia, mild weight gain, mild cough, and insulin antibodies were more frequent with inhaled insulin than with oral agent therapy alone. Pulmonary function was similar in all groups. LIMITATIONS: This study evaluated only patients with hemoglobin A1c levels of 8% to 11%, did not compare inhaled insulin with other insulins or oral therapy except a dual regimen of secretagogue and sensitizer, and lasted only 12 weeks. CONCLUSIONS: Inhaled insulin improved overall glycemic control and hemoglobin A1c level when added to or substituted for dual oral agent therapy with an insulin secretagogue and sensitizer. Consistent with other insulin therapies, hypoglycemia and mild weight gain occurred. Pulmonary function showed no between-group differences.

Diabetes Incidence and Glucose Tolerance after Termination of Pioglitazone Therapy: Results from ACT NOW.

CONTEXT: Thiazolidinediones have proven efficacy in preventing diabetes in high-risk individuals. However, the effect of thiazolidinediones on glucose tolerance after cessation of therapy is unclear. OBJECTIVE: To examine the effect of pioglitazone (PIO) on incidence of diabetes after discontinuing therapy in ACT NOW. Design, Settings and Patients: Two-hundred ninety-three subjects (placebo [PLAC], n = 138; PIO, n = 152) completed a median followup of 11.7 mo after study medication was stopped. RESULTS: Diabetes developed in 138 (12.3%) of PLAC vs 17 of 152 PIO patients (11.2%; P = not significant, PIO vs PLAC). However, the cumulative incidence of diabetes from start of study medication to end of washout period remained significantly lower in PIO vs PLAC (10.7 vs 22.3%; P < .005). After therapy was discontinued, 23.0% (35/152) of PIO-treated patients remained normal-glucose tolerant (NGT) vs 13.8% (19/138) of PLAC-treated patients (P = .04). Insulin secretion/insulin resistance index (I0-120/G0-120 × Matsuda index) was markedly lower in subjects with impaired glucose tolerance (IGT) who converted to diabetes during followup vs those who remained IGT or NGT. The decline in-cell function (insulin secretion/insulin resistance index) was similar in subjects with IGT who developed diabetes, irrespective of whether they were treated with PIO or PLAC. CONCLUSIONS: 1) The protective effect of PIO on incidence of diabetes attenuates after discontinuation of therapy, 2) cumulative incidence of diabetes in individuals exposed to PIO remained significantly (56%) lower than PLAC and a greater number of PIO-treated individuals maintained NGT after median followup of 11.4 mo, and 3) low insulin secretion/insulin resistance index is a strong predictor of future diabetes following PIO discontinuation.

Pioglitazone is equally effective for diabetes prevention in older versus younger adults with impaired glucose tolerance.

To determine the efficacy of pioglitazone to prevent type 2 diabetes in older compared to younger adults with pre-diabetes. Six hundred two participants with impaired glucose tolerance (IGT) were randomized in double blind fashion to placebo or pioglitazone for diabetes prevention in the ACT NOW study (NEJM 364:1104-1115, 2011). Cox proportional hazard regression was used to compare time to development of diabetes over a mean of 2 years between older (≥61 years) and younger participants. We compared effects of pioglitazone versus placebo on metabolic profiles, inflammatory markers, adipokines, ß cell function (disposition index), insulin sensitivity (Matsuda index), and body composition by ANOVA. Diabetes incidence was reduced by 85 % in older and 69 % in younger subjects (p = 0.41). ß cell function (disposition index) increased by 35.0 % in the older and 26.7 % in younger subjects (p = 0.83). Insulin sensitivity (Matsuda index) increased by 3.07 (5.2-fold) in older and by 2.54 (3.8-fold) in younger participants (p = 0.58). Pioglitazone more effectively increased adiponectin in older versus younger subjects (22.9 ± 3.2 µg/mL [2.7-fold] vs. 12.7 ± 1.4 µg/mL [2.2-fold], respectively; p = 0.04). Younger subjects tended to have a greater increase in whole body fat mass compared to older subjects (3.6 vs. 3.1 kg; p = 0.061). Younger and older subjects had similar decreases in bone mineral density (0.018 ± 0.0071 vs. 0.0138 ± 0.021 g/cm2). Younger and older pre-diabetic adults taking pioglitazone had similar reductions in conversion to diabetes and older adults had similar or greater improvements in metabolic risk factors, demonstrating that pioglitazone is useful in preventing diabetes in older adults.

A novel insulin resistance index to monitor changes in insulin sensitivity and glucose tolerance: the ACT NOW study.

OBJECTIVE: The objective was to test the clinical utility of Quantose M(Q) to monitor changes in insulin sensitivity after pioglitazone therapy in prediabetic subjects. Quantose M(Q) is derived from fasting measurements of insulin, α-hydroxybutyrate, linoleoyl-glycerophosphocholine, and oleate, three nonglucose metabolites shown to correlate with insulin-stimulated glucose disposal. RESEARCH DESIGN AND METHODS: Participants were 428 of the total of 602 ACT NOW impaired glucose tolerance (IGT) subjects randomized to pioglitazone (45 mg/d) or placebo and followed for 2.4 years. At baseline and study end, fasting plasma metabolites required for determination of Quantose, glycated hemoglobin, and oral glucose tolerance test with frequent plasma insulin and glucose measurements to calculate the Matsuda index of insulin sensitivity were obtained. RESULTS: Pioglitazone treatment lowered IGT conversion to diabetes (hazard ratio = 0.25; 95% confidence interval = 0.13-0.50; P < .0001). Although glycated hemoglobin did not track with insulin sensitivity, Quantose M(Q) increased in pioglitazone-treated subjects (by 1.45 [3.45] mg·min(-1)·kgwbm(-1)) (median [interquartile range]) (P < .001 vs placebo), as did the Matsuda index (by 3.05 [4.77] units; P < .0001). Quantose M(Q) correlated with the Matsuda index at baseline and change in the Matsuda index from baseline (rho, 0.85 and 0.79, respectively; P < .0001) and was progressively higher across closeout glucose tolerance status (diabetes, IGT, normal glucose tolerance). In logistic models including only anthropometric and fasting measurements, Quantose M(Q) outperformed both Matsuda and fasting insulin in predicting incident diabetes. CONCLUSIONS: In IGT subjects, Quantose M(Q) parallels changes in insulin sensitivity and glucose tolerance with pioglitazone therapy. Due to its strong correlation with improved insulin sensitivity and its ease of use, Quantose M(Q) may serve as a useful clinical test to identify and monitor therapy in insulin-resistant patients.

Oral modified insulin (HIM2) in patients with type 1 diabetes mellitus: results from a phase I/II clinical trial.

An effective, orally administered insulin product would be of substantial benefit in the treatment of patients with diabetes mellitus. This phase I/II clinical trial was the first to investigate the safety and effectiveness of a single oral dose of a modified human insulin in controlling postprandial plasma glucose levels in patients with type 1 diabetes mellitus who were receiving basal continuous subcutaneous insulin infusion (CSII) therapy. Fourteen patients with type 1 diabetes mellitus were evaluated in an open-label, 2-center, dose-escalation, nonrandomized study of oral hexyl-insulin monoconjugate 2 (HIM2). After an overnight fast and prior to receiving a standardized meal (50% carbohydrates, 30% fat, 20% proteins; 650 calories), the patients received either no additional insulin (day 1), or 0.5 to 1.0 mg/kg of HIM2 (day 2). All patients received a basal insulin regimen by CSII throughout the study. Blood samples were collected for determination of glucose and insulin levels for 240 minutes post-dose. The postprandial glucose excursion versus time curves showed clear reductions in glucose values after both HIM2 doses (day 2) relative to no treatment (day 1), although the differences in the reductions were not statistically significant. When the data for both HIM2 doses were pooled, a statistically significant effect of HIM2 on glucose excursion (as measured by AUCex(30-240)) was observed. Mean +/- SD values for AUCex(30-240) were 501.35 +/- 124.1 mg. h/dL after no treatment and 375.81 +/- 215.5 mg. h/dL after HIM2 (Wilcoxon signed-rank test, P =.042). The results of this study suggest that oral HIM2, when added to a basal insulin regimen, was safe and may prove effective in controlling postprandial hyperglycemia in patients with type 1 diabetes mellitus. Further clinical investigation is necessary.

Oral insulin product hexyl-insulin monoconjugate 2 (HIM2) in type 1 diabetes mellitus: the glucose stabilization effects of HIM2.

This study was designed to determine plasma glucose and insulin levels after administration of three escalating doses of the oral insulin product hexyl-insulin monoconjugate 2 (HIM2) in fasting, insulin-deprived adult patients with type 1 diabetes. The study was also designed to assess the safety of the product. Sixteen patients with daily insulin requirements of 27-60 units and glycosylated hemoglobin levels of 5.8-11.1% completed the study. Patients' regular insulin regimens were discontinued at bedtime, and they fasted overnight. Blood glucose levels were stabilized overnight by intravenous insulin infusion. In the morning, intravenous insulin was discontinued 30 min prior to an oral dose of HIM2 (0.6, 0.8, or 1.0 mg/kg). A second oral dose of HIM2 was administered 120 min later. Plasma glucose and insulin levels were measured during a 240-min evaluation period after the first HIM2 dose. Identical HIM2 dosing and study procedures were repeated 1 week later with the same patients. Stable or declining plasma glucose levels were observed on 31 out of a total of 32 dosing days beginning at 20 min after the initial administration of HIM2. After plasma glucose levels declined or were stable for 30 min to 2 h, increases were observed for some patients. However, for the majority of patients (68.8%), plasma glucose levels were <150% of predose levels throughout the postdose evaluation period. Similar results were observed after repeating the study procedures 1 week later. Also, plasma glucose area under the concentration-time curves (AUCs) were inversely correlated with plasma insulin AUCs. HIM2 appeared to be safe and well-tolerated in this study; no episodes of symptomatic hypoglycemia were observed. Thus, HIM2 prevented the expected rise in plasma glucose concentrations in insulin-deprived adult patients with type 1 diabetes. The lack of hypoglycemic events in this exploratory study is encouraging and suggests that there may be less risk of severe hypoglycemia associated with HIM2 when compared with injectable insulin. The promising data in this study support the hypothesis that oral HIM2 reproduces the physiological pathway of insulin secreted by the pancreas - through the portal vein directly to the liver - suggesting a therapeutic advantage in the management of type 1 diabetes mellitus.